Statistics from Altmetric.com
A possible new therapeutic strategy for preventing exacerbations
Asthma is an extremely common illness which affects an estimated 300 million people of all ages and ethnic backgrounds worldwide with significant costs for healthcare systems.1 The clinical course of the disease is characterised by acute episodes of worsening of symptoms and decrease in lung function known as exacerbations. Prevention of exacerbations has been the goal of most therapeutic interventions developed so far because exacerbations seriously affect the quality of life of patients and their families.2 The clinical presentation of asthma exacerbations may be extremely heterogeneous; they can be rapid in onset or occur more gradually. The severity of asthma exacerbations is also extremely variable, ranging from mild episodes to severe attacks which result in respiratory failure and may ultimately lead to death.
Airway inflammation is a characteristic feature consistently present in patients with asthma from the early stages in children3 to elderly people.4 The inflammatory process has been extensively investigated in stable conditions, showing an increased infiltration of eosinophils, mast cells and CD4 T lymphocytes characterised by a Th2 profile, with release of cytokines such as interleukin (IL)-4, IL-5, IL-13, eotaxin and RANTES.5 Conversely, little is known about the cellular mechanisms activated during exacerbations and, in particular, in severe exacerbations.
In this issue of Thorax (see p 475), Qiu et al6 investigated the inflammatory response in bronchial biopsy specimens taken from patients admitted to hospital with a severe exacerbation of asthma and who required intubation for respiratory failure. They found that, during severe exacerbations, there was an increase in eosinophils and an even greater increase in neutrophils, resulting in similar final numbers of the two granulocyte subtypes infiltrating the airways. These results confirm previous observations on sputum7 and bronchoalveolar lavage fluid in acute severe asthma.8 A unique quality of the study by Qiu et al is that, unlike the other studies, it examined bronchial biopsy specimens obtained during exacerbations. This provides direct information on the airway tissue where inflammatory responses take place and interact with smooth muscle and mucus-secreting cells, thus contributing to airway narrowing.
Tissue inflammation in severe exacerbations of asthma has been evaluated previously, but only at post mortem examination. The pathological abnormalities observed in the airways of subjects who suffered a fatal asthma attack included both eosinophil and neutrophil infiltration.9 In particular, neutrophils predominated in those patients who died suddenly after onset of the attack, while eosinophils were more frequent in fatal events with a slow onset.10,11 It has been proposed that these differences in the inflammatory profile may reflect the dynamics of inflammatory cell recruitment in the airways, with the neutrophil being the predominant cell in the early phase following an inflammatory stimulus and the eosinophil being the predominant cell in the late phase.11 However, it was unclear whether these observations truly reflected the cellular mechanisms underlying the severe exacerbation or were rather due to death-related events. The study by Qiu et al sheds some light on this issue by confirming that infiltration of neutrophils and eosinophils are indeed characteristic features of severe exacerbations of asthma.
Interestingly, in a previous paper the same authors reported that both granulocyte subtypes were increased even in severe exacerbations of chronic obstructive pulmonary disease (COPD).12 Moreover, they showed that airway neutrophilia in COPD was driven by upregulation of the chemoattractants CXCL5 (ENA-78) and CXCL8 (IL-8) and of their type I receptor (CXCR1). When they tested the hypothesis that these chemoattractants may also be crucial in exacerbations of asthma, they found that only CXCL5 was significantly upregulated during exacerbations compared with stable asthma. While CXCL8 binds to both CXCR1 and CXCR2, CXCL5 binds preferentially to CXCR213 and, indeed, the increased expression of CXCL5 was paralleled by upregulation of CXCR2 in this study. These observations suggest that activation of the CXCL5/CXCR2 axis is a crucial event in the pathogenesis of asthma exacerbations and identifies a new potential target for anti-inflammatory strategies.
One of the most intriguing findings in this study is that, at variance with COPD, in exacerbations of asthma CXCL5 and CXCR2 were correlated with the number of eosinophils infiltrating the airways rather than with neutrophils. Of interest, human eosinophils may produce CXCL5 in vitro, an effect that is particularly evident after prolonged incubation with tumour necrosis factor α (TNFα).14 Since there is evidence that TNFα is increased in severe asthma,15,16 and especially in status asthmaticus,17 it can be hypothesised that even in vivo TNFα may induce CXCL5 upregulation by eosinophils. This in turn would drive activation of CXCR2-bearing cells such as neutrophils, thus promoting their recruitment at sites of inflammation. In this context, there is promising evidence that therapeutic strategies aimed at interfering with TNFα signalling may be beneficial in patients with refractory asthma,15,16 especially by reducing exacerbations,18 although this requires confirmation in larger controlled studies.19
We should be careful in interpreting the findings of Qiu et al for several reasons. First, patients with an exacerbation received corticosteroids intravenously as part of the exacerbation management and most of them had been treated with inhaled or oral corticosteroids before the exacerbations. Moreover, the subjects examined were not well matched with regard to age, since patients with an exacerbation were older than those with stable asthma and were mechanically ventilated before biopsy sampling. All these factors could have potentially enhanced airway neutrophilia.20,21
More importantly, this is a cross-sectional rather than a longitudinal study, so the possibility that neutrophilia was already present in those subjects before occurrence of severe exacerbations cannot be ruled out. Indeed, most of the patients with an asthma exacerbation had severe disease treated with high doses of inhaled or oral corticosteroids, while patients with stable asthma had mild disease controlled only with β2-agonists on an as needed basis. This difference in the degree of severity may have influenced the inflammatory cell profile in the patients with stable asthma since there is evidence that tissue neutrophilia is more frequent in severe asthma.22
Despite these unavoidable limitations, the report by Qiu et al is important because it promotes a better understanding of the events contributing to the development of severe exacerbations. Indeed, this study provides the framework for the cellular changes occurring in the airway tissue and the molecular mechanisms responsible for inflammatory cell recruitment. As a consequence, these observations will encourage new research into therapeutic strategies to prevent exacerbations, one of the most important aims of asthma management.
A possible new therapeutic strategy for preventing exacerbations
Competing interests: None.